4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5 dimethylbenzonitrile, Etravirine (I), is marketed under the brand name of INTELENCE by Tibotec.

INTELENCE is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). Reverse transcriptase is a viral DNA polymerase enzyme that HIV needs to reproduce. Intelence blocks the enzymatic function of reverse transcriptase and prevents completion of synthesis of the double-stranded viral DNA, thus preventing HIV from multiplying.
Etravirine and its production method were first reported in U.S. Pat. No. 7,037,917. This method of synthesizing Etravirine describes treating 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile with NH3 in the presence of 1,4-dioxane in a pressure vessel at 150° C. for 4 days.
Drugs of the Future 2005, 30(5): 462-468 discloses that 4-guanidinobenzonitrile is cyclized with diethylmalonate by means of sodium ethoxide to give 4-(4,6-dihydroxypyrimidine-2-yl-amino)-benzonitrile, which upon treatment with POCl3 yields the corresponding dichloro derivative. Further bromination with bromine and sodium bicarbonate in aqueous methanol affords 4-(5-bromo-4,6-dichloropyrimidin-2-ylamine)-benzonitrile, which on condensation with the sodium salt of cyano-2,6-dimethylphenolate in presence of N-methylpyrrolidone and dioxane gives 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile, followed by the aminolysis of the same intermediate yields Etravirine. It also discloses another process in which 5-bromo-2,4,6-trichloropyrimidine is reacted with 4-aminobenzonitrile in presence of diisopropylethylamine to give 4-(5-Bromo-4,6-dichloro-pyrimidin-2-ylamino)-benzonitrile, which is then reacted with 4-hydroxy-3,5-dimethylbenzonitrile to give 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]benzonitrile. The aminolysis of the same intermediate yields Etravirine.
WO 2010150279 describes a process for the formation of Etravirine, comprising condensation of 2,4,6-trichloropyrimidine with 3,5-dimethyl-4-hydroxybenzonitrile to give 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5-dimethyl benzonitrile, which is condensed with 4-aminobenzonitrile. Aminolysis of the resulting compound followed by halogenation gives Etravirine.
The prior art processes for preparing Etravirine involve aminolysis. The reaction of a desired intermediate with ammonia even in refluxing dioxane requires more time for reaction completion. Therefore, there exists a need in the art for an improved process for the preparation of Etravirine, which is safe and commercially viable.
The present invention relates to a novel process for the preparation of Etravirine, which is commercially viable, less time cycle comparatively with prior art processes and it also provides novel intermediates which are useful in the preparation of Etravirine.